Several recent lines of evidence have paved the way for an increased role for immune based therapies in the treatment of HIV infection. Not withstanding the important role played by anti-retrovirals in the management of HIV infection, it becomes increasingly apparent that therapies aimed only at controlling viral replication could not have the expected long term effects namely efficient control of viral replication. Indeed these therapies have led to specific immune component is severely impaired. Indeed the immune system is systematically destroyed at several levels from the onset of primary infection with the progressive disappearance of HIV specific helper cells, clonal exhaustion of HIV specific, CTLs and the emergence of immune escape mutants combined with the destruction of the lymph nodes architecture, the site where all immune responses are initiated. It becomes important to identify strategies which can re-educate the immune system control viral replication. Enhancement of HIV specific immune responses can be achieved through vaccination with HIV antigens. However, in order to ensure that these immunizations will lead to diverse and persistent immune responses, it becomes important to introduce into such immune interventions in humans (specific aims 1 and 3) and macaques on the reconstitution of the immune system (specific aim 2, 4 and 5). We will focus on the capacity of therapeutic vaccination to induce the generation and persistence of CD4T cells to novel epitopes using class II oligomeric molecules and T cell receptor specific probes. The complexity of homeostatic processes of the immune system several have led us to test several types of immune modulators for the development of a therapeutic vaccine. We will compare the effect of therapeutic vaccination administered together with several types of immune modulators (cytokines and costimulatory molecules) in the macaque model on the qualitative and quantitative features of immune reconstitution. We will be in a position to identify the requirements for broad and persistent immune reconstitution. Altogether the experiments outlined in this project should allow us to identify therapeutic regimen which will allow a better control of the residual viremia by settling the homeostasis of the immune system through the presence of a strong helper cell compartment.